A colleague read the article (below) and asked the following question :
" Is not "4 grays, or 400 rads" a high dose, not a "low-level radiation dose"? After all, 1 Sv = 1 Gray x Quality Factor, and QF depends upon the type of ionizing radiation (1 for x-rays, gamma rays, electrons; 20 for alphas, according to the ICRP, 1977). Certainly on a whole-body irradiation, 400 rem (400 rads x QF of 1) would be a high dose and would induce severe effects if it was an acute dose. Of course the researchers here were dealing with individual cells, not a whole body dose. Any health physicists out there to explain this apparent difference in terminology between low and high dose? "
Thanks in advance for your help.
Jaro
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Posted on the Berkeley Lab email news release on February 15, 2002 and at:
http://www.lbl.gov/Science-Articles/Archive/LSD-Barcellos-Hoff.html
NEW FINDINGS ON BREAST CANCER REPORTED AT ANNUAL MEETING OF
THE AMERICAN ASSOCIATION FOR THE ADVACEMENT OF SCIENCE
Contact: Lynn Yarris, (510)486-5375, lcyarris@lbl.gov
BERKELEY, CA -- New experimental findings by Lawrence Berkeley National
Laboratory (Berkeley Lab) cell biologist Mary Helen Barcellos-Hoff show
that exposure to ionizing radiation creates a microenvironment in the
tissue surrounding breast cells that can cause even nonirradiated cells
and their progeny to become cancerous. The discovery suggests new and
possibly more effective means for preventing breast cancer.
Speaking in Boston at the annual meeting of the American Association for
the Advancement of Science (AAAS), Barcellos-Hoff described her study in
which a special line of nonirradiated, nonmalignant breast cells were
transplanted into irradiated mammary glands. Nearly 75 percent of the
transplanted glands developed tumors, and the effect persisted up to 14
days after the radiation exposure. Tumors developed in less than 20
percent of the glands when Barcellos-Hoff transplanted the same type of
cells into nonirradiated mice.
"Our studies demonstrate that radiation elicits rapid and persistent
global alterations in the mammary gland microenvironment," says
Barcellos-Hoff. "We believe that these radiation-induced
microenvironments lead to changes in the physical characteristics
(phenotypes) of cells and their progeny that promote carcinogenesis. In
other words, radiation exposure can cause breast cancer by pathways
other than genetic mutations."
Studies by Barcellos-Hoff and her research group indicate that one of
these alternative pathways is damage to the
tissue that surrounds a breast cell. This surrounding tissue, which
includes a network of fibrous and globular proteins called the
extracellular matrix (ECM), normally acts to suppress cells from
becoming cancerous.
"Repairing damaged tissue so that it once again suppresses instead of
promotes carcinogenesis is a simpler strategy for stopping the cancer
process, compared to trying to repair individual damaged cells," says
Barcellos-Hoff. "Our data is pointing to the tissue surrounding breast
cells as a primary target of ionizing radiation damage."
Ionizing radiation is a well-established carcinogen, but previous
studies of its cancer-causing effects have largely focused on damage to
the breast cells' DNA. If repaired improperly, this damage gives rise to
genetic mutations or chromosome damage that if passed on to daughter
cells leads to cancer. In that context, the question for medical
researchers has been: How do cells become cancerous?
Barcellos-Hoff has pursued a different tack. "It takes a tissue to make
a tumor," she says. "Cells don't become
tumors without cooperation from the surrounding tissue. Cancer is a
process that occurs at the tissue level and the question we ought to be
asking is: How do tissues become tumors?"
To answer that question, Barcellos-Hoff and her group, which includes
postdoctoral fellow Rhonda Henshall-Powell, have focused their attention
on the extracellular signaling that takes place between a cell and the
microenvironment of its surrounding tissue. Their studies and others
have shown that proper communications between the cell and its
microenvironment are crucial to normal functioning. The director of
Berkeley Lab's Life Sciences Division, Mina Bissell, has shown that
breakdown in these communications can initiate the cancer process or
cause an abnormally high rate of apoptosis programmed cell death another
significant factor in the development of breast and other cancers.
"Ionizing radiation is like a wound, in that it produces a defensive
response from the affected tissue. Usually this helps to protect
undamaged cells and eliminates those that have become abnormal,"
Barcellos-Hoff says. "However, if there is too much damage, the defense
response can become a problem."
For example, exposure to just the right dose of ultraviolet radiation
will cause skin tissue to respond by producing melanin, the protective
skin-darkening pigment. Too much exposure at once, however, leads to
sunburn, and repeated exposures over time will damage the tissue,
causing wrinkles and possibly skin cancer. In the case of mammary glands
exposed to low doses of ionizing radiation, the surrounding tissue has
been programmed to send signals to the cells that would suppress genomic
mutations and cause cell apoptosis. But as the exposure intensifies, the
defense program becomes "corrupted" and the wrong signals get transmitted.
"We hypothesize that under certain conditions, radiation exposure
prevents normal cell interactions, which in turn predisposes susceptible
cells to genomic instability that can result in mutations," Barcellos-Hoff says.
In their study with cells transplanted into irradiated mammary glands,
Barcellos-Hoff and senior research associate Shraddha Ravani exposed
specially created epithelium-free glands (mouse epithelium develops
postnatally and is readily removed from the gland) to low-level
radiation doses (4 grays, or 400 rads). Upon observing the persistent
carcinogenic effects on the transplanted cells, they established that
the radiation damage to the tissue was generating signals that altered
how the cells' genomes were expressed. This resulted in the creation of
a new cell phenotype with physical characteristics that were cued by the
extracellular signals to act cancerous. Breast cells acquiring the new
phenotypes passed these characteristics onto their daughter cells.
"Genomes are like the keys on a piano, in that the same keys can be used
to play a wide variety of music," says Barcellos-Hoff. "In our studies,
the ionizing radiation elicited changes in how the genomes of the
transplanted cells were being expressed by changing the extracellular
signals they were receiving."
Barcellos-Hoff and her colleagues now want to identify the altered
signals that are being sent from the irradiated tissue to the cells and
determine the mechanism by which these signals are destabilizing breast
cell genomes. To do so they are using a model of organized human breast
cells developed by Bissell.
In her AAAS talk Barcellos-Hoff also discussed the preliminary findings
of a study on which she is working in collaboration with Bissell and
radiation oncologist Catherine Park. The team has found that irradiated
human breast cells also show persistent phenotypic changes that affect
their ability to interact with other cells. Such behavior is typical of cancer cells.
For images related to this research, visit
http://www.lbl.gov/Science-Articles/Archive/LSD-Barcellos-Hoff.html
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